期刊
EMBO JOURNAL
卷 36, 期 13, 页码 1963-1980出版社
WILEY
DOI: 10.15252/embj.201695679
关键词
differentiation; epidermal progenitor cell; skin; tumorigenesis
资金
- National Institutes of Health [R01-AR063630, AA021434, AA020265]
- Research Scholar Grant from the American Cancer Society [RSG-13-198-01]
- V scholar award from V Foundation
- National Basic Research Program of China (973 Program) [2014CBA02004]
- Shanghai Municipal Science and Technology Commission [15410723100]
- University of Chicago molecular and cellular biology training grant [T32, GM007183]
Tissue homeostasis of skin is sustained by epidermal progenitor cells localized within the basal layer of the skin epithelium. Posttranslational modification of the proteome, such as protein phosphorylation, plays a fundamental role in the regulation of stemness and differentiation of somatic stem cells. However, it remains unclear how phosphoproteomic changes occur and contribute to epidermal differentiation. In this study, we survey the epidermal cell differentiation in a systematic manner by combining quantitative phosphoproteomics with mammalian kinome cDNA library screen. This approach identified a key signaling event, phosphorylation of a desmosome component, PKP1 (plakophilin-1) by RIPK4 (receptor-interacting serine-threonine kinase 4) during epidermal differentiation. With genome-editing and mouse genetics approach, we show that loss of function of either Pkp1 or Ripk4 impairs skin differentiation and enhances epidermal carcinogenesis in vivo. Phosphorylation of PKP1's N-terminal domain by RIPK4 is essential for their role in epidermal differentiation. Taken together, our study presents a global view of phosphoproteomic changes that occur during epidermal differentiation, and identifies RIPK-PKP1 signaling as novel axis involved in skin stratification and tumorigenesis.
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